1-[3-6-Fluoro-1,2-benzisoxazol-3-yl)propyl]-4-hydroxy-4-phenylpiperidines to treat psychoses

ABSTRACT

Novel 1-[3-(6-fluoro-1,2-benzisoxazol-3-yl)propyl]-4-hydroxy-4-phenylpiperidines, processes for the preparation thereof, and methods of treating psychoses and alleviating pain employing compounds and compositions thereof are disclosed.

This is a division, of application Ser. No. 366,247 filed Apr. 9, 1982now, U.S. Pat. No. 4,396,770.

DESCRIPTION OF THE INVENTION

The present invention relates to novel1-[3-(1,2-benzisoxazol-3-yl)propyl]-4-hydroxy-4-phenylpiperidines. Moreparticularly, the present invention relates to1-[3-(6-fluoro1,2-benzisoxazol-3-yl)propyl]-4-phenyl-4-hydroxypiperidinesof formula 1, ##STR1## wherein X is hydrogen, loweralkyl, loweralkoxy,halogen or trifluoromethyl; Y is hydrogen or trifluoromethyl with theproviso that Y is hydrogen when X is hydrogen, loweralkyl, loweralkoxyor trifluoromethyl and Y is hydrogen, trifluoromethyl when X is halogen;the optical antipodes thereof, or pharmaceutically acceptable additionsalts thereof, which are useful for treating psychoses and alleviatingpain, alone or in combination with inert psychoses treating and painalleviating adjuvants.

Preferred1-[3-(1,2-benzisoxazol-3-yl)propyl]-4-hydroxy-4-phenylpiperidines arethose wherein X is halogen and Y is hydrogen. Most preferred are thosewherein the halogen is bound to the 4-position of the benzene ring.

As used through the specification and appended claims, the term "alkyl"refers to a straight or branched chain hydrocarbon radical containing nounsaturation and having 1 to 7 carbon atoms such as methyl, ethyl,1-propyl, 2-propyl, 1-butyl, 1-pentyl, 2-pentyl, 3-hexyl, 4-heptyl andthe like; the term "alkoxy" refers to a monovalent substituent whichconsists of an alkyl group linked through an ether oxygen and having itsfree valence bond from the ether oxygen such as methoxy, ethoxy,propoxy, butoxy, 1,1-dimethylethoxy, pentoxy, 3-methylpentoxy,2-ethylpentoxy and the like; the term "halogen" refers to a member of afamily consisting of chlorine, fluorine, bromine or iodine. The term"lower" as applied to any of the aforementioned groups refers to a grouphaving a carbon skeleton containing up to and including 5 carbon atoms.

The compounds of the present invention which lack an element of symmetryexist as optical antipodes and as the racemic forms thereof. The opticalantipode may be prepared from the corresponding racemic forms bystandard optical resolution techniques, involving, for example, theseparation of diastereomeric salts of those instant compoundscharacterized by the presence of a basic amino group and an opticallyactive acid, or by the synthesis from optically active precursors.

The present invention comprehends all optical isomers and racemic formsthereof. The formulas of the compounds shown herein are intended toencompass all possible optical isomers of the compounds so depicted.

The novel1-[3-(6-fluoro-1,2-benzisoxazol-3-yl)propyl]-4-hydroxy-4-phenylpiperidinesof formula 1, the compounds of the present invention, are prepared bycondensing a Grignard reagent of formula 2 ##STR2## wherein X and Y areas before, prepared by conventional method from a bromobenzene offormula 3 ##STR3## wherein X and Y are as before with magnesium (see,for example, M. S. Kharasch, "Grignard Reactions of NonmetallicSubstances", Prentice Hall, New York, 1954, Chapter II), with1-[3-(6-fluoro-1,2-benzisoxazol-3-yl)propyl[-4-piperidone of formula 4##STR4## the synthesis of which is described in U.S. patent applicationSer. No. 366,245 filed Apr. 9, 1983. The condensation is convenientlyperformed by treating the piperidone 4 with the Grignard reagent 2 in asuitable solvent. Among suitable solvents there may be mentionedethereal solvents such as, for example, diethyl ether, dimethoxyethane,dimethoxyethoxyethane, dioxane, tetrahydropyran and tetrahydrofuran.Tetrahydrofuran is preferred.

The condensation temperature is not narrowly critical. It is desirable,however, to conduct the condensation at a temperature within the rangeof about -10° C. to about 40° C. to assure a reasonable rate ofconversion. A condensation temperature of about ambient temperature ispreferred.

Alternatively, the compounds of the present invention, the1-[3-(6-fluoro-1,2-benzisoxazol-3-yl)propyl]-4-hydroxy-4-phenylpiperidinesof formula 1, are prepared by condensing3-(3-chloropropyl)-6-fluoro-1,2-benzisoxazole of formula 5 ##STR5## thesynthesis of which is described in U.S. patent application Ser. No.257,698, filed Apr. 27, 1981, with readily available4-hydroxy-4-phenylpiperidines of formula 6 ##STR6## wherein X and Y areas above. The condensation is conveniently performed by treating thehalide 5 with the piperidine 6 in the presence of an acid acceptor, adisplacement promotor and a suitable solvent. Among acid acceptors,there may be mentioned alkali metal carbonates and alkali metalbicarbonates such as, for example, lithium carbonate, sodium carbonateand potassium carbonate, and lithium bicarbonate, sodium bicarbonate andpotassium bicarbonate. Potassium carbonate and sodium bicarbonate arepreferred. Among displacement promotors, there may be mentioned alkalimetal halides such as, for example, sodium iodide and potassium iodide,and sodium bromide and potassium bromide. Potassium iodide is preferred.Among suitable solvents, there may be mentioned polar aprotic substancessuch as, for example, dimethylformamide, dimethylacetamide andhexamethylphosphoramide. Dimethylformamide is preferred. The temperatureat which the condensation is conducted is not narrowly critical. It isdesirable, however, to perform the condensation at a temperature withinthe range of about 50° C. to about 130° C. to assure a reasonable rateof conversion. A reaction temperature within the range of about 70° C.to 110° C. is preferred.

The1-[3-(6-fluoro-1,2-benzisoxazol-3-yl)propyl]-4-hydroxy-4-phenylpiperidinesof the present invention are useful as analgesic agents due to theirability to alleviate pain in mammals which is demonstrated in thephenyl-para-quinone writhing assay in mice, a standard assay foranalgesia [Proc. Soc. Exptl. Biol. Med., 95, 729 (1953)]. Presented inTable 1 is the analgesic activity of representative compounds of theinvention and two standards, expressed as the estimated subcutaneousdose at which the mice experience a 50% reduction in phenyl-para-quinoneinduced writhes, i.e., the ED₅₀ -value.

                  TABLE 1                                                         ______________________________________                                                               Analgesic Activity                                     Compound               (ED.sub.50 mg/kg)                                      ______________________________________                                        1-[3-(6-Fluoro-1,2-benzisoxazol-                                                                     5.9                                                    3-yl)propyl]-4-hydroxy-4-phenyl-                                              piperidine                                                                    1-[3-(6-Fluoro-1,2-benzisoxazol-                                                                     0.8                                                    3-yl)propyl]-4-(3-chlorophenyl)-                                              4-hydroxypiperidine hydrochloride                                             1-[3-(6-Fluoro-1,2-benzisoxazol-                                                                     3.8                                                    3-yl)propyl]-4-hydroxy-4-(4-meth-                                             oxyphenyl)piperidine hydrochloride                                            1-[3-(6-Fluoro-1,2-benzisoxazol-                                                                     6.2                                                    3-yl)propyl]-4-(4-fluorophenyl)-                                              4-hydroxypiperidine                                                           1-[3-(6-Fluoro-1,2-benzisoxazol-                                                                     1.0                                                    3-yl)propyl]-4-hydroxy-4-(3-tri-                                              fluoromethylphenyl)piperidine                                                 hydrochloride                                                                 propoxyphene (standard)                                                                              3.9                                                    pentazocin (standard)  1.3                                                    ______________________________________                                    

Analgesia production is achieved when the present1-[3-(6-fluoro-1,2-benzisoxazol-3-yl)propyl]-4-hydroxy-4-phenylpiperidinesare administered to a subject requiring such treatment as an effectiveoral, parenteral or intravenous dose of from 0.01 to 50 mg/kg of bodyweight per day. A particularly effective amount is about 25 mg/kg ofbody weight per day. It is to be understood, however, that for anyparticular subject, specific dosage regimens should be adjustedaccording to the individual need and the professional judgment of theperson administering or supervising the administration of the aforesaidcompound. It is to be further understood that the dosages set forthherein are exemplary only and that they do not, to any extent, limit thescope or practice of the invention.

The1-[3-(6-fluoro-1,2-benzisoxazol-3-yl)propyl]-4-hydroxy-4-phenylpiperidinesof the present invention are useful for treating psychoses by virtue oftheir ability to block apomorphine-induced climbing in mammals.

Antipsychotic activity is determined in the climbing mice assay by amethod similar to those described by P. Protais et al.,Psychopharmacol., 50, 1 (1976) and B. Costall, Eur. J. Pharmacol., 50,39 (1978).

The subject CK-1 male mice (23-27 grams) are group-housed under standardlaboratory conditions. The mice are individually placed in wire meshstick cages (4"×4"×10") and are allowed one hour for adaptation andexploration of the new environment. Then apomorphine is injectedsubcutaneously at 1.5 mg/kg, a dose causing climbing in all subjects for30 minutes. Compounds to be tested for antipsychotic activity areinjected intraperitoneally 30 minutes prior to the apomorphine challengeat a screening dose of 10 mg/kg.

For evaulation of climbing, 3 readings are taken at 10, 20 and 30minutes after apomorphine administration according to the followingscale:

    ______________________________________                                        Climbing Behavior        Score                                                ______________________________________                                        Mice with:                                                                    4 paws on bottom (no climbing)                                                                         0                                                    2 paws on the wall (rearing)                                                                           1                                                    4 paws on the wall (full climb)                                                                        2                                                    ______________________________________                                    

Mice consistently climbing before the injection of apomorphine will bediscarded.

With full-developed apomorphine climbing, the animals are hanging ontothe cage walls, rather motionless, over longer periods of time. Bycontrast, climbs due to mere motor stimulation usually only last a fewseconds.

The climbing scores are individually totaled (maximal score: 6 per mouseover 3 readings) and the total score of the control group (vehicleintraperitoneally-apomorphine subcutaneously) is set to 100%. ED₅₀values with 95% confidence limits are calculated by a Linear RegressionAnalysis. Antipsychotic activity expressed as the ED₅₀ value ofrepresentative1-[3-(6-fluoro-1,2-benzisoxazol-3-yl)propyl]-4-hydroxy-4-phenylpiperidinesas well as two standard antipsychotics are presented in Table II.

                  TABLE II                                                        ______________________________________                                                              Antipsychotic Activity                                  Compound              ED.sub.50 (mg/kg)                                       ______________________________________                                        4-(4-chlorophenyl)-1-[3-(6-                                                                         0.51                                                    fluoro-1,2-benzisoxazol-3-yl)-                                                propyl]-4-hydroxypiperidine                                                   1-[3-(6-fluoro-1,2-benzisoxazol-                                                                    9.6                                                     3-yl)propyl]-4-hydroxy-4-phenyl-                                              piperidine                                                                    1-[3-(6-fluoro-1,2-benzisoxazol-                                                                    0.56                                                    3-yl)propyl]-4-hydroxy-4-(4-tolyl)-                                           piperidine                                                                    1-[3-(6-fluoro-1,2-benzisoxazol-                                                                    3.1                                                     3-yl)propyl]-4-hydroxy-4-(4-tri-                                              fluoromethylphenyl)piperidine                                                 1-[3-(6-fluoro-1,2-benzisoxazol-                                                                    0.8                                                     3-yl)propyl]-4-(3-chlorophenyl)-                                              4-hydroxypiperidine hydrochloride                                             1-[3-(6-fluoro-1,2-benzisoxazol-                                                                    0.8                                                     3-yl)propyl]-4-(4-fluorophenyl)-                                              4-hydroxypiperidine                                                           1-[3-(6-fluoro-1,2-benzisoxazol-                                                                    0.25                                                    3-yl)propyl]-4-hydroxy-4-(3-tri-                                              fluoromethylphenyl)piperidine                                                 hydrochloride                                                                 1-[3-(6-fluoro-1,2-benzisoxazol-                                                                    8.3                                                     3-yl)propyl]-4-hydroxy-4-(2-methyl-                                           phenyl)piperidine hydrochloride                                               haloperidol (standard)                                                                              0.11                                                    sulpiride (standard)  4.5                                                     ______________________________________                                    

Antipsychotic activity is achieved when the present1-[3-(6-fluoro-1,2-benzisoxazol-3-yl)propyl]-4-hydroxy-4-phenylpiperidinesare administered to a subject requiring such treatment as an effectiveoral, parenteral or intravenous dose of from 0.01 to 50 mg/kg of bodyweight per day. A particularly preferred effective amount is about 25mg/kg of body weight per day. It is to be understood, however, that forany particular subject, specific dosage regimens should be adjusted tothe individual need and the professional judgment of the personadministering or supervising the administration of the aforesaidcompound. It is to be further understood that the dosages set forthherein are exemplary only and they do not, to any extent, limit thescope or practice of the invention.

Effective amounts of the compounds of the invention may be administeredto a subject by any one of various methods, for example, orally as incapsule or tablets, parenterally in the form of sterile solutions orsuspensions, and in some cases intravenously in the form of sterilesolutions. The free base final products, while effective themselves, maybe formulated and administered in the form of their pharmaceuticallyacceptable addition salts for purposes of stability, convenience ofcrystallization, increased solubility and the like.

Preferred pharmaceutically acceptable addition salts include salts ofmineral acids, for example, hydrochloric acid, sulfuric acid, nitricacid and the like, salts of monobasic carboxylic acids such as, forexample, acetic acid, propionic acid and the like, salts of dibasiccarboxylic acids such as, for example, maleic acid, fumaric acid, oxalicacid and the like, and salts of tribasic carboxylic acids such as, forexample, carboxysuccinic acid, citric acid and the like.

The active compounds of the present invention may be administeredorally, for example, with an inert diluent or with an edible carrier.They may be enclosed in gelatin capsules or compressed into tablets. Forthe purpose of oral therapeutic administration, the aforesaid compoundsmay be incorporated with excipients and used in the form of tablets,troches, capsules, elixirs, suspensions, syrups, wafers, chewing gumsand the like. These preparations should contain at least 0.5% of activecompound, but may be varied depending upon the particular form and mayconveniently be between 4% to about 75% of the weight of the unit. Theamount of present compound in such composition is such that a suitabledosage will be obtained. Preferred compositions and preparationsaccording to the present invention are prepared so that an oral dosageunit form contains between 1.0-300 mgs of active compound.

The tablets, pills, capsules, troches and the like may also contain thefollowing ingredients: a binder such as microcrystalline cellulose, gumtragacanth or gelatin; an excipient such as starch or lactose, adisintegrating agent such as alginic acid, Primogel, corn starch and thelike; a lubricant such as magnesium stearate or Sterotes; a glidant suchas colloidal silicon dioxide; amd a sweetening agent such as sucrose orsaccharin or a flavoring agent such as peppermint, methyl salicylate, ororange flavoring may be added. When the dosage unit form is a capsule,it may contain, in addition to materials of the above type, a liquidcarrier such as a fatty oil. Other dosage unit forms may contain othervarious materials which modify the physical form of the dosage unit, forexample, as coatings. Thus tablets or pills may be coated with sugar,shellac, or other enteric coating agents. A syrup may contain, inaddition to the active compounds, sucrose as a sweetening agent andcertain preservatives, dyes and colorings and flavors. Materials used inpreparing these various compositions should be pharmaceutically pure andnon-toxic in the amounts used.

For the purposes of parenteral therapeutic administration, the activecompounds of the invention may be incorporated into a solution orsuspension. These preparations should contain at least 0.1% of theaforesaid compound, but may be varied between 0.5 and about 50% of theweight thereof. The amount of active compound in such compositions issuch that a suitable dosage will be obtained. Preferred compositions andpreparations according to the present invention are prepared so that aparenteral dosage unit contains between 0.5 to 100 mgs of the activecompound.

The solutions or suspensions may also include the following components:a sterile diluent such as water for injection, saline solution, fixedoils, polyethylene glycols, glycerine, propylene glycol or othersynthetic solvents; antibacterial agents such as benzyl alcohol ormethyl parabens; antioxidants such as ascorbic acid or sodium bisulfite;chelating agents such as ethylenediaminetetraacetic acid; buffers suchas acetates, citrates or phosphates and agents for the adjustment oftonicity such as sodium chloride or dextrose. The parenteral preparationcan be enclosed in ampoules, disposable syringes or multiple dose vialsmade of glass or plastic.

The following Examples are for illustrative purposes only and are not tobe construed as limiting the invention.

EXAMPLE 11-[3-(6-Fluoro-1,2-benzisoxazol-3-yl)propyl]-4-hydroxy-4-phenylpiperidine

To 50 ml of dry dimethylformamide was added, 6.0 g of4-hydroxy-4-phenylpiperidine, 8.0 g of3-(3-chloropropyl)-6-fluoro-1,2-benzisoxazole, 13.0 g of sodiumbicarbonate, and a few crystals of potassium iodide. After stirring at80° C. for one hr, the mixture was cooled, filtered, and the filtrateevaporated to an oil. The oil was stirred with 100 ml water for fivemins, and then extracted with ether/ethyl acetate. The organic layer waswashed with water (2×), saturated sodium chloride solution and driedover anhydrous magnesium sulfate. After filtering, the solvents wereevaporated. Trituration with ether gave 3.0 g (25%) of product, mp133°-137° C. Recrystallization twice from ethyl ether gave theanalytical sample, mp 138°-139° C.

Analysis: Calculated for C₂₁ H₂₃ FN₂ O₂ : 71.16%C; 6.54%H; 7.91%N.Found: 71.34%C; 6.51%H; 7.66%N.

EXAMPLE 24-(3-Chlorophenyl)-1-[3-(6-fluoro-1,2-benzisoxazol-3-yl)propyl]-4-hydroxypiperidinehydrochloride

To a suspension of 1.2 g of magnesium shavings and a few drops ofdibromoethane in 30 ml of ether was added a solution of 8.7 g of3-bromochlorobenzene in 20 ml of ether at such a rate so as to maintainreflux. After the addition was complete, the mixture was diluted with 30ml of tetrahydrofuran and then a solution of 6.3 g of1-[3-(6-fluoro-1,2-benzisoxazol-3-yl)propyl]-4-piperidone in 30 ml oftetrahydrofuran was slowly added. After one hr, the mixture was dilutedwith ether, poured into 400 ml of saturated ammonium chloride solutionand extracted with ether. The organic extracts were washed with water(2×), saturated sodium chloride solution and dried over anhydrousmagnesium sulfate, filtered and concentrated to an oil. The oil wasconverted to 8.5 g (88%) of product, mp 170°-172° C., by treatment withethereal hydrogen chloride. An analytical sample was obtained byrecrystallization from ethyl acetate/methanol and had, mp 188°- 189° C.

Analysis: Calculated for C₂₁ H₂₂ ClFN₂ O₂.HCl: 59.30%C; 5.45%H. Found:59.52%C; 5.56%H.

EXAMPLE 34-(4-Chlorophenyl)-1-[3-(6-fluoro-1,2-benzisoxazol-3-yl)propyl]-4-hydroxypiperidine

To 30 ml of dry dimethylformamide was added 3.0 g of4-(4-chlorophenyl)-4-hydroxypiperidine, 2.99 g of3-(3-chloropropyl)-6-fluoro-1,2-benzisoxazole, 8.0 g of sodiumbicarbonate, and a crystal of potassium iodide. After stirring at 90° C.for one hr, the mixture was evaporated to an oil. The oil was stirredwith 100 ml of water for five mins, and then extracted with ether. Theether solution was washed with water (2×), saturated sodium chloridesolution and dried over anhydrous magnesium sulfate. After filtering,the solvent was evaporated. Recrystallization of the residue from ethylether gave 3.6 g of product, mp 142°-145° C. The analytical sample wasobtained by recrystallization from ethyl ether and had mp 148°-150° C.

Analysis: Calculated for C₂₁ H₂₂ ClFN₂ O₂ : 64.86%C; 5.70%H; 7.21%N.Found: 64.75%C; 5.64%H; 7.15%N.

EXAMPLE 41-[3-(6-Fluoro-1,2-benzisoxazol-3-yl)propyl]-4-(4-fluorophenyl)-4-hydroxypiperidine

To a suspension of 1.1 g of magnesium shavings and a few drops ofdibromoethane in 30 ml of ether was added a solution of 7.9 g ofp-bromofluorobenzene in 20 ml of ether at a rate to maintain reflux ofthe mixture. After the addition was complete, the mixture was slowlydiluted with 30 ml of tetrahydrofuran and then a solution of 5 g of1-[3-(6-fluoro-1,2-benzisoxazol-3-yl)propyl]-4-piperidone in 30 ml oftetrahydrofuran was slowly added. After one hr, the mixture was dilutedwith ether, poured into 400 ml of saturated ammonium chloride solutionand extracted with ether. The organic extracts were washed with water(2×), saturated sodium chloride solution and dried over anhydrousmagnesium sulfate, filtered and concentrated. The residue wasrecrystallized from hexanes/ether to give 3.6 g (54%) of product, mp100°-101° C.

Analysis: Calculated for C₂₁ H₂₂ F₂ N₂ O₂ : 67.72%C; 5.95%H. Found:67.88%C; 5.67%H.

EXAMPLE 51-[3-(6-Fluoro-1,2-benzisoxazol-3-yl)propyl]-4-hydroxy-4-(2-methylphenyl)piperidinehydrochloride

To a suspension of 0.9 g of magnesium shavings and a few drops ofdibromoethane in 30 ml of ether was added a solution of 6.2 g of2-bromotoluene in 30 ml of ether. After the addition was complete, themixture was stirred under reflux for one hr, cooled, and a solution of 5g of 1-[3-(6-fluoro-1,2-benzisoxazol-3-yl)propyl]-4-piperidone in 50 mlof tetrahydrofuran was added. After one hr, the mixture was diluted withether, poured into 400 ml of saturated ammonium chloride solution andextracted with ether. The organic extracts were washed with water (2×),saturated sodium chloride solution and dried over anhydrous magnesiumsulfate, filtered and concentrated. The residue was converted to 6.4 g(82%) of product by treatment with ethereal hydrogen chloride.Recrystallization from ethyl acetate/methanol gave the analyticalsample, mp 191°-192° C. (dec).

Analysis: Calculated for C₂₂ H₂₅ FN₂ O₂.HCl: 65.26%C; 6.47%H. Found:65.14%C; 6.62%H.

EXAMPLE 61-[3-(6-Fluoro-1,2-benzisoxazol-3-yl)propyl]-4-(4-tolylpiperidine

To 50 ml of diethyl ether was added a solution of 15 ml ofp-tolylmagnesium bromide (1.96 M in ether). The resultant solution wascooled to 0° C. with an ice-bath and a solution of 5.3 g of1-[3-(6-fluoro-1,2-benzisoxazol-4-yl)propyl]-4-piperidone in 50 ml ofether was added over a period of thirty mins, with stirring. The mixturewas stirred at ambient temperature for two hrs, poured into 500 ml ofice-cold ammonium chloride solution, stirred for five mins and extractedwith ether/ethyl acetate. The organic layer was washed with water (2×),saturated sodium chloride solution and dried over anhydrous magnesiumsulfate. After filtering, the solvents were evaporated. Crystallizationof the residue from ethyl ether gave 2.6 g (36%) of product, mp 96°-99°C. Recrystallization from ethyl ether gave the analytical sample, mp98°-100° C.

Analysis: Calculated for C₂₂ H₂₅ FN₂ O₂ : 71.71%C; 6.84%H; 7.61%N.Found: 71.81%C; 6.85%H; 7.56%N.

EXAMPLE 71-[3-(6-Fluoro-1,2-benzisoxazol-3-yl)propyl]-4-hydroxy-4-(4-methoxyphenyl)piperidinehydrochloride

A solution of 6.3 g of1-[3-(6-fluoro-1,2-benzisoxazol-3-yl)propyl]-4-piperidone in 35 ml oftetrahydrofuran was slowly added to a solution of 49 ml ofp-anisylmagnesium bromide (1.4 M in tetrahydrofuran). After the additionwas complete, the reaction mixture was stirred at ambient temperaturefor one hr, diluted with ether, poured into 400 of ml saturated ammoniumchloride solution and extracted with ether. The organic extracts werewashed with water (2×), saturated sodium chloride solution and driedover anhydrous magnesium sulfate, filtered and concentrated. The residuewas converted to 8.5 g (89%) of product, mp 100°-105° C., by treatmentwith ethereal hydrogen chloride. An analytical sample was obtained byrecrystallization from ethyl acetate/methanol and had mp 181°-182° C.(dec).

Analysis: Calculated for C₂₂ H₂₅ FN₂ O₃.HCl: 62.77%C; 6.23%H. Found:63.04%C; 6.35%H.

EXAMPLE 81-[3-(6-Fluoro-1,2-benzisoxazol-3-yl)propyl]-4-hydroxy-4-(3-trifluoromethylphenyl)piperidinehydrochloride

To a suspension of 1.1 g of magnesium shavings and a few drops ofdibromoethane in 30 ml of ether was added a solution of 9.8 g of3-bromobenzotrifluoride in 30 ml of ether at a rate to maintain refluxof the mixture. After the magnesium was consumed, a solution of 6 g of1-[3-(6-Fluoro-1,2-benzisoxazol-3-yl)propyl]-4-piperidone in 500 ml oftetrahydrofuran was slowly added. After one hr, the mixture was dilutedwith ether, poured into 400 ml of saturated ammonium chloride solutionand extracted with ether. The organic extracts were washed with water(2×), saturated sodium chloride solution and dried over anhydrousmagnesium sulfate, filtered and concentrated. Treatment of the residuewith ethereal hydrogen chloride gave a salt. Recrystallization fromethyl acetate/methanol gave 4 g (55%) of product, mp 214°-215° C.

Analysis: Calculated for C₂₂ H₂₂ F₄ N₂ O₂.HCl: 57.58%C; 5.05%H. Found:57.48%C; 5.04%H.

EXAMPLE 91-[3-(6-fluoro-1,2-benzisoxazol-3-yl)propyl]-4-hydroxy-4-(4-trifluoromethylphenyl)piperidine

To a suspension of 1.2 g of magnesium shavings and a few drops ofdibromoethane in 30 ml of ether was added a solution of 10.3 g of4-bromobenzotrifluoride in 20 ml of ether at such a rate so as tomaintain reflux of the mixture. After the addition was complete, themixture was diluted with 35 ml of tetrahydrofuran, and a solution of 6.3g of 1-[3-(6-fluoro-1,2-benzisoxazol-3-yl)propyl]-4-piperidone in 50 mlof tetrahydrofuran was slowly added. After one hr, the mixture wasdiluted with ether, poured into 400 ml of saturated ammonium chloridesolution and extracted with ether. The organic extracts were washed withwater (2×), saturated sodium chloride solution and dried over anhydrousmagnesium sulfate, filtered and concentrated. Trituration withhexane/ether gave 7 g (73%) of product, mp 150°-152° C.Recrystallization from ether gave the analytical sample, mp 152°-153° C.

Analysis: Calculated for C₂₂ H₂₂ F₄ N₂ O₂ : 62.55%C; 5.25%H; 6.63%N.Found: 62.38%C; 5.19%H; 6.84%N.

EXAMPLE 104-(4-Chloro-3-trifluoromethylphenyl)-1-[3-(6-fluoro-1,2-benzisoxazol-3-yl)propyl]-4-hydroxypiperidinehydrochloride

To a suspension of 0.9 g of magnesium shavings and a few drops ofdibromoethane in 30 ml of ether was added a solution of 9.4 of5-bromo-2-chlorobenzotrifluoride in 30 ml of ether at a rate to maintainreflux. After the magnesium was consumed a solution of 5 g of1-[3-(6-fluoro-1,2-benzisoxazol-3-yl)propyl]-4-piperidone in 50 ml oftetrahydrofuran was added. After thirty mins the reaction mixture waspoured into 400 ml of saturated ammonium chloride solution and extractedwith ethyl acetate/ether. The organic extracts were washed with water(2×), saturated sodium chloride solution and dried over anhydrousmagnesium sulfate, filtered and concentrated to an oil, which waspurified by column chromatography (silic gel, tetrahydrofuran). Thedesired fractions were combined and concentrated to an oil, which wasconverted to a salt by treatment with ethereal hydrogen chloride.Recrystallization from ethyl acetate/methanol gave 3 g (34%) of product,mp 203°-204° C.

Analysis: Calculated for C₂₂ H₂₁ ClF₄ N₂ O₂.HCl: 53.56%C; 4.50%H. Found:53.53%C; 4.35%H.

EXAMPLE 114-(4-Bromophenyl)-1-[3-(6-fluoro-1,2-benzisoxazol-3-yl)propyl]-4-hydroxypiperidine

To 25 ml of ethyl ether was added 1.0 g of magnenesium turnings, 0.5 mlof 1,2-dibromoethane and a few drops of a solution of 9.4 g of1,4-dibromobenzene in 50 ml of ethyl ether. The reaction was initiatedwith heat and maintained by the addition of the solution of1,4-dibromobenzene. The resultant solution was stirred at ambienttemperature for fifteen mins and then a solution of 7.0 g of1-[3-(6-fluoro-1,2-benzisoxazol-3-yl)propyl]-4-piperidone in 50 ml oftetrahydrofuran was added with vigorous stirring. After the addition wascomplete, the mixture was stirred at ambient temperature for thirty minsand then poured into an ice cold solution of ammonium chloride. Afterdilution with 200 ml of ethyl ether, the organic layer was collected,washed with water (2×), saturated sodium chloride solution and thendried over anyhydrous magnesium sulfate. After filtering, the solventswere evaporated to an oil, which was triturated with petroleum ether.The resultant precipitate was collected and dried to give 4.4 g (41%) ofproduct, mp 138°-145° C. Recrystallization four times from ethyl ethergave the analytical sample, mp 150°-151° C.

Analysis: Calculated for C₂₁ H₂₂ BrFN₂ O₂ : 58.20%C; 5.12%H; 6.47%N.Found: 58.66%C; 5.20%H; 6.44%N.

We claim:
 1. A method of treating psychoses comprising administering toa mammal in need of psychoses treatment a psychoses treating effectiveamount of a compound of the formula ##STR7## wherein X is hydrogen,loweralkyl of 1 to 5 carbon atoms, loweralkoxy of 1 to 5 carbon atoms,halogen or trifluoromethyl; Y is hydrogen or trifluoromethyl with theproviso that Y is hydrogen when X is hydrogen, loweralkyl of 1 to 5carbon atoms, loweralkoxy of 1 to 5 carbon atoms, or trifluoromethyl andY is hydrogen or trifluoromethyl when X is halogen; the optical antipodethereof; or a pharmaceutically acceptable acid addition salt thereof. 2.A method of treating psychoses according to claim 1 wherein X is halogenand Y is hydrogen.
 3. A method of treating psychoses according to claim2 wherein the halogen is bound to the 4-position of the benzene ring. 4.The method of treating psychoses according to claim 3 wherein thecompound is4-(4-chlorophenyl)-1-[3-(6-fluoro-1,2-benzisoxazol-3-yl)propyl]-4-hydroxypiperidine.5. The method of treating psychoses according to claim 3 wherein thecompound is1-[3-(6-fluoro-1,2-benzisoxazol-3-yl)propyl]-4-(4-fluorophenyl)-4-hydroxypiperidine.6. A psychoses treating composition comprising an inert psychosestreating adjuvant and, as the active ingredient, an amount effective intreating psychoses of a compound of the formula ##STR8## wherein X ishydrogen, loweralkyl of 1 to 5 carbon atoms, loweralkoxy of 1 to 5carbon atoms, halogen or trifluoromethyl; Y is hydrogen ortrifluoromethyl with the proviso that Y is hydrogen when X is hydrogen,loweralkyl of 1 to 5 carbon atoms, loweralkoxy of 1 to 5 carbon atoms,or trifluoromethyl and Y is hydrogen or trifluoromethyl when X ishalogen; the optical antipode thereof, or a pharmaceutically acceptableacid addition salt thereof.
 7. A psychoses treating compositionaccording to claim 6 wherein X is halogen and Y is hydrogen.
 8. Apsychoses treating composition according to claim 7 wherein the halogenis bound to the 4-position of the benzene ring.
 9. A psychoses treatingcomposition according to claim 8 wherein the active ingredient is4-(4-chlorophenyl)-1-[3-(6-fluoro-1,2-benzisoxazol-3-yl)propyl]-4-hydroxypiperidine.10. A psychoses treating composition according to claim 8 wherein theactive ingredient is1-[3-(6-fluoro-1,2-benzisoxazol-3-yl)propyl]-4-(4-fluorophenyl)-4-hydroxypiperidine.